Abstract
Reducing body weight to improve metabolic health and related comorbidities is a primary goal in treating obesity1,2.
However, maintaining weight loss is a considerable challenge, especially as the body seems to retain an obesogenic memory that defends against body weight changes 3,4.
Overcoming this barrier for long-term treatment success is difficult because the molecular mechanisms underpinning this phenomenon remain largely unknown.
Here, by using single-nucleus RNA sequencing, we show that both human and mouse adipose tissues retain cellular transcriptional changes after appreciable weight loss.
Furthermore, we find persistent obesity-induced alterations in the epigenome of mouse adipocytes that negatively affect their function and response to metabolic stimuli.
Mice carrying this obesogenic memory show accelerated rebound weight gain, and the epigenetic memory can explain future transcriptional deregulation in adipocytes in response to further high-fat diet feeding.
In summary, our findings indicate the existence of an obesogenic memory, largely on the basis of stable epigenetic changes, in mouse adipocytes and probably other cell types. These changes seem to prime cells for pathological responses in an obesogenic environment, contributing to the problematic ‘yo-yo’ effect often seen with dieting. Targeting these changes in the future could improve long-term weight management and health outcomes.
Main
Obesity and its related comorbidities represent substantial health risks. A primary clinical objective in managing obesity is to achieve appreciable weight loss (WL), typically through rigorous dietary and lifestyle interventions, pharmaceutical treatments or bariatric surgery (BaS). Strategies relying on behavioural and dietary changes frequently only result in short-term WL and are susceptible to the ‘yo-yo’ effect, in which individuals regain weight over time. This recurrent pattern may be partially attributable to an (obesogenic) metabolic memory that persists even after notable WL or metabolic improvements. Indeed, lasting phenotypic changes from previous metabolic states, that is, metabolic memory, have been reported in mouse adipose tissue (AT) or the stromal vascular fraction (SVF), whereas in liver these were reversible. Persistent alterations after WL in the immune compartment, and transcriptional and functional memory of obesity in endothelial cells of many organs, have also been reported.
Epigenetic mechanisms and modifications are essential for development, differentiation and identity maintenance of adipocytes in vitro and in vivo, but are also expected to be crucial contributors to the cellular memory of obesity. For example, lasting chromatin accessibility changes have been associated with pathological memory of obesity in mouse myeloid cells and, also, cold exposure studies have indicated the existence of (epigenetic) cellular memory. Hitherto, most human studies have focused on DNA methylation analysis in bulk tissues or whole blood to assess putative cellular memory. These reports might be confounded by variations in cell type composition, which are poorly characterized in the AT during WL, and therefore serve foremost as indicators of cellular epigenetic memory.
In summary, it remains unresolved whether individual cells retain a metabolic memory and whether it is conferred through epigenetic mechanisms. Here, we set out to address this by first performing single-nucleus RNA sequencing (snRNA-seq) of AT from individuals living with obesity before and after significant WL, as well as lean, obese and formerly obese mice, confirming the presence of retained transcriptional changes, and, second, by characterizing the epigenome of mouse adipocytes, which revealed the long-term persistence of an epigenetic obesogenic memory.
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Link: https://www.nature.com/articles/s41586-024-08165-7
Source: Nature
Published: 18 November 2024
Authors: Laura C. Hinte, Daniel Castellano-Castillo, Adhideb Ghosh, Kate Melrose, Emanuel Gasser, Falko Noé, Lucas Massier, Hua Dong, Wenfei Sun, Anne Hoffmann, Christian Wolfrum, Mikael Rydén, Niklas Mejhert, Matthias Blüher & Ferdinand von Meyenn
Note: Nutrigenomics Institute is not responsible for the opinions expressed in this article.
